L655,240, acting as a competitive BACE1 inhibitor, efficiently decreases beta-amyloid peptide production in HEK293-APPswe cells

doi:10.1038/aps.2012.74

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 生物技术药物研发中心（筹）

	L655,240, acting as a competitive BACE1 inhibitor, efficiently decreases beta-amyloid peptide production in HEK293-APPswe cells
	Lu, Qin 3; Chen, Wu-yan 2; Zhu, Zhi-yuan 2; Chen, Jing2 ; Xu, Ye-chun2 ; Kaewpet, Morakot 1,4; Rukachaisirikul, Vatcharin 1,4; Chen, Li-li2 ; Shen, Xu2,3
刊名	ACTA PHARMACOLOGICA SINICA
	2012-12
卷号	33 期号:12 页码:1459-1468
关键词	L655,240 Alzheimer's disease BACE1 beta-amyloid peptide HEK293-APPswe cells
ISSN号	1671-4083
DOI	10.1038/aps.2012.74
文献子类	Article
英文摘要	Aim: To identify a small molecule L655,240 as a novel beta-secretase (BACE1) inhibitor and to investigate its effects on beta-amyloid (A beta) generation in vitro. Methods: Fluorescence resonance energy transfer (FRET) was used to characterize the inhibitory effect of L655,240 on BACE1. Surface plasmon resonance (SPR) technology-based assay was performed to study the binding affinity of L655,240 for BACE1. The selectivity of L655,240 toward BACE1 over other aspartic proteases was determined with enzymatic assay. The effects of L655,240 on A beta 40, A beta 42, and sAPP beta production were studied in HEK293 cells stably expressing APP695 Swedish mutant(K595N/M596L) (HEK293-APPswe cells). The activities of BACE1, gamma-secretase and alpha-secretase were assayed, and both the mRNA and protein levels of APP and BACE1 were evaluated using real-time PCR (RT-PCR) and Western blot analysis. Results: L655,240 was determined to be a competitive, selective BACE1 inhibitor (IC50 = 4.47 +/- 1.37 mu mol/L), which bound to BACE1 directly (K-D=17.9+/-0.72 mu mol/L). L655,240 effectively reduced A beta 40, A beta 42, and sAPP beta production by inhibiting BACE1 without affecting the activities of gamma-secretase and alpha-secretase in HEK293-APPswe cells. L655,240 has no effect on APP and BACE1 mRNA or protein levels in HEK293-APPswe cells. Conclusion: The small molecule L655,240 is a novel BACE1 inhibitor that can effectively decreases A beta production in vitro, thereby highlighting its therapeutic potential for the treatment of Alzheimer's disease.
资助项目	State Key Program of Basic Research of China[2010CB912501] ; National Natural Science Foundation of China[81173105] ; National Natural Science Foundation of China[30890044] ; Science Foundation of Shanghai[11XD1406100] ; Science Foundation of Shanghai[11ZR1444500] ; Foundation of the Chinese Academy of Sciences[KSCX2-EW-Q-3]
WOS关键词	PROSTAGLANDIN ENDOPEROXIDE ANTAGONIST ; ALZHEIMERS-DISEASE ; PRECURSOR PROTEIN ; MEMORY DEFICITS ; SELECTIVE THROMBOXANE ; SECRETASE INHIBITOR ; TRANSGENIC MICE ; MOUSE MODEL ; IDENTIFICATION ; THERAPEUTICS
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
CSCD记录号	CSCD:4694092
出版者	ACTA PHARMACOLOGICA SINICA
WOS记录号	WOS:000312003500002
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277859]
专题	生物技术药物研发中心（筹）中科院受体结构与功能重点实验室新药研究国家重点实验室药理学第三研究室
通讯作者	Chen, Li-li
作者单位	1.Prince Songkla Univ, Fac Sci, Ctr Innovat Chem, Hat Yai, Thailand; 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 3.E China Univ Sci & Technol, Sch Pharm, Shanghai 200237, Peoples R China; 4.Prince Songkla Univ, Dept Chem, Hat Yai, Thailand
推荐引用方式 GB/T 7714	Lu, Qin,Chen, Wu-yan,Zhu, Zhi-yuan,et al. L655,240, acting as a competitive BACE1 inhibitor, efficiently decreases beta-amyloid peptide production in HEK293-APPswe cells[J]. ACTA PHARMACOLOGICA SINICA,2012,33(12):1459-1468.
APA	Lu, Qin.,Chen, Wu-yan.,Zhu, Zhi-yuan.,Chen, Jing.,Xu, Ye-chun.,...&Shen, Xu.(2012).L655,240, acting as a competitive BACE1 inhibitor, efficiently decreases beta-amyloid peptide production in HEK293-APPswe cells.ACTA PHARMACOLOGICA SINICA,33(12),1459-1468.
MLA	Lu, Qin,et al."L655,240, acting as a competitive BACE1 inhibitor, efficiently decreases beta-amyloid peptide production in HEK293-APPswe cells".ACTA PHARMACOLOGICA SINICA 33.12(2012):1459-1468.